Production of unit dose constructs

ABSTRACT

Dissolvable unit dose constructs and their method of manufacture are disclosed in which the unit dose constructs are formed of a composition including a polymer matrix that includes a water soluble polymer, active ingredient, and a liquid carrier. The composition is deposited directly, such as by stenciling, to form individual unit doses without the need to cut and convert long, continuous rolls of film.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of, and priority to, U.S. Prov. App.Nos. 61/755,495 and 61/755,492, both of which were filed on Jan. 23,2013, and each of which are hereby incorporated by reference in theirentirety.

FIELD

The present application is directed toward the field of drug deliveryand more particularly to methods of producing unit dose constructs fordrug delivery.

BACKGROUND

Fast-dissolving drug-delivery systems were first developed in the late1970s as an alternative to tablets, capsules and syrups for pediatric,geriatric and other patients who experience difficulties swallowingtraditional oral solid-dosage forms. In response to this need, a varietyof orally disintegrating tablet (ODT) formats were commercialized. MostODT products were formulated to dissolve in less than one minute whenexposed to saliva to form a solution that could then be more easilyswallowed.

More recently, dissolvable oral thin films (OTFs) emerged from theconfection and oral care markets in the form of breath strips. Theseproducts became a widely accepted form by consumers for deliveringvitamins and personal care products and subsequently for also deliveringother active ingredients, including pharmaceuticals.

Pharmaceutical companies and consumers alike have embraced OTFs as apractical and accepted alternative to traditional medicine forms such asliquids, tablets, and capsules. OTFs offer fast, accurate dosing in asafe, efficacious format that is convenient and portable, without theneed for water or measuring devices. OTFs are typically the size of apostage stamp and disintegrate on a patient's tongue in a matter ofseconds for the rapid release of one or more active pharmaceuticalingredients (APIs). More broadly, the use of thin films has expanded toinclude a variety of products that are manufactured and used for a widerange of transmucosal drug delivery within the oral cavity as well asvia other mucosal interfaces.

Known methods of dissolvable film production involve casting the liquidformulation as a continuous film, sheet or web in the form of wide andlong rolls on a continuous substrate (e.g. paper or polyester linerswhich may or may not have release coatings) to form what is sometimesreferred to as a master roll. The manufacturing process includes dryingthe liquid formulation to remove solvents (aqueous and/or non-aqueous)to yield the thin film on the substrate. The master rolls thus formedare then converted into smaller unit doses through a combination of rollslitting and individual unit dose die-cutting, as well as transferringthose doses from the manufacturing substrate to the product's primarypackaging.

Despite the move toward drug delivery by dissolvable tablets and films,numerous drawbacks and disadvantages still exist with such products andthere are a variety of commercial needs in the field that have not yetbeen met.

SUMMARY

Exemplary embodiments are directed to dissolvable unit dose constructsfor transmucosal drug delivery (oral and otherwise) including, but notlimited to, dissolvable films, wafers and tablets and the production ofthe same that address currently existing, but unmet needs. Moreparticularly, exemplary embodiments are directed to improvementsrelating to unit dose manufacture of those constructs.

According to an exemplary embodiment, a method of forming a dissolvableunit dose construct comprises providing a muco-adhesive compositioncomprising a polymer matrix, the polymer matrix comprising a watersoluble polymer, the composition further comprising an active ingredientand a liquid carrier, the composition in the form of a thixotropicpaste; stenciling the paste onto a substrate to deposit the compositionas a plurality of individual dosage units; and removing at least aportion of the liquid carrier from the individual dosage units.

According to another exemplary embodiment, a method of forming adissolvable unit dose construct comprises providing a muco-adhesivecomposition comprising a polymer matrix, the polymer matrix comprising awater soluble polymer, the composition further comprising an activeingredient and a liquid carrier; depositing the composition onto asubstrate as a plurality of individual dosage units; and vacuum dryingthe individual dosage units to remove at least a portion of the liquidcarrier.

According to yet another exemplary embodiment, a method of forming adissolvable unit dose construct comprises providing a first compositioncomprising a water soluble polymer and a liquid carrier; depositing thefirst composition onto a substrate; providing a second compositioncomprising a water soluble polymer and a liquid carrier; stenciling thesecond composition at a plurality of discrete locations overlying thefirst composition; and removing at least a portion of the liquid carrierfrom the first and second compositions to form a multi-layer unit doseconstruct.

According to still another exemplary embodiment, a method of forming adissolvable unit dose construct comprises providing at least onemuco-adhesive composition comprising a polymer matrix, the polymermatrix comprising a water soluble polymer, the composition furthercomprising an active ingredient and a liquid carrier; depositing thecomposition onto a substrate as a first individual dosage unit;depositing a second individual dosage unit onto the substrate adjacentthe first individual dosage unit; and removing liquid carrier from theindividual dosage units, wherein the first and second individual unitsare distinct from one another in volume, composition, or other physicalor chemical property.

According to still another exemplary embodiment, a method of forming adissolvable unit dose construct comprises providing a first compositioncomprising a water soluble polymer and a liquid carrier; depositing thefirst composition onto a substrate to form a plurality of individualunits; providing a second composition comprising a water solublepolymer, an active ingredient and a liquid carrier; depositing thesecond composition overlying a portion of an individual unit of thefirst composition; providing a third composition comprising a watersoluble polymer, an active ingredient of an identity different from theactive ingredient of the second composition, and a liquid carrier;depositing the third composition overlying a portion of the individualunit of the first composition different from the portion overlain by thesecond composition; and removing at least a portion of the liquidcarrier from the compositions to form a multi-layer unit dose construct.

An advantage of certain exemplary embodiments includes that the use ofindividually formed doses limits variation of the active ingredientbetween dosage units. Particularly in the case of stenciling, advantagesinclude the ability to deliver readily an appropriate deposit thicknessfor the construct being formed. Openings in the stencil mask define avolume of paste with which the openings in the stencil are filled andprovides a more uniform deposit of the construct formulation. The use ofstenciling also permits the use of a more viscous formulation, such as athixotropic paste. As a result, a wider variety of constructs can becreated, as the paste is better able to hold its shape enabling theformation of thicker individually formed unit does constructs includingwafers and tablets, in addition to films.

Another advantage of certain exemplary embodiments is that vacuum dryingin unit dose construct production can provide faster drying times atlower temperatures that, in-turn, affords improved productivity, lowerenergy consumption and improved stability, as well as reducing potentialfor entrapped air or bubble defects. The combination of cooling withvacuum drying can also yield a lyophilization effect.

Another advantage of certain exemplary embodiments includes that theability to place different size active areas on a commonly sized backinglayer using the same production equipment across production runs or evenwithin the same production run.

An advantage of certain exemplary embodiments includes the ability togenerate multiple adjacent constructs of different levels or types ofactive for in-line production of a drug regimen as a group ofdissolvable films or other unit dose construct.

Still another advantage of certain exemplary embodiments includes theability to incorporate multiple actives into a single unit doseconstruct, even if those active ingredients would otherwise beincompatible with one another, through discrete deposition of thoseactive ingredients at separate locations on a common carrier.

Other features and advantages of the present invention will be apparentfrom the following more detailed description of exemplary embodiments,taken in conjunction with the accompanying drawings which illustrate, byway of example, the principles of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an exemplary system for producing unit doseconstructs in accordance with exemplary embodiments.

FIG. 1A illustrates an exemplary system for producing unit doseconstructs in accordance with an exemplary embodiment showing depositionin regimen format.

FIG. 2 illustrates an exemplary stencil set up for use in conjunctionwith exemplary embodiments.

FIG. 3 illustrates a package for a unit dose construct in accordancewith an exemplary embodiment.

FIG. 4 illustrates a unit dose construct in accordance with an exemplaryembodiment.

FIGS. 5A and 5B illustrate a unit dose construct in accordance withanother exemplary embodiment.

FIG. 6 illustrates a unit dose construct in accordance with an exemplaryembodiment.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Exemplary embodiments are directed to unit dosage forms for oral andother transmucosal drug delivery. While described primarily with respectto films, and more particularly those constructs known within the art asthin films (films having a thickness between 0.1 mils and 10 mils),other dissolvable muco-adhesive constructs are also contemplated by thepresent disclosure and the exemplary embodiments described herein. Suchadditional unit dose constructs include, without limitation, thick films(films having a thickness greater than 10 mils), wafers and tablets.

The composition of the films and other unit dose constructs discussed inthe context of exemplary embodiments can be characterized broadly as aliquid-base biologically compatible muco-adhesive polymer matrixcontaining an active ingredient that forms an erodible, disintegrableand/or dissolvable construct upon drying and may include, withoutlimitation, the films described in U.S. Pat. No. 7,470,397, which isincorporated by reference in its entirety. It will be appreciated thatthe resulting constructs have a combination of a solid contentsufficient to provide strength to aid in handling but balanced toprovide disintegration at a predetermined rate.

Any suitable polymers may be employed as the matrix of the unit doseconstructs in accordance with exemplary embodiments. It will beappreciated that the polymer(s) selected for any particular constructmay depend on a variety of factors, including the active ingredient tobe incorporated, the desired rate of disintegration (which may bemodified with or without the use of a surfactant), and the rheology ofthe liquid formulation, as well as other factors known to those ofordinary skill in the art for producing conventional drug deliveryconstructs.

The polymer(s) may be water soluble, water swellable, water insoluble,or a combination thereof and may include cellulose or a cellulosederivative. Although the use of water swellable and water insolublepolymers is contemplated, the formulation contains a sufficient amountof water soluble polymer to ensure the eventual disintegration of thesubsequently formed film.

Exemplary polymers for the muco-adhesive matrix include water-solublehydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, sodiumcarboxy methyl cellulose, methyl cellulose, polyvinyl alcohol, sodiumalginate, polyethylene glycol, polyethylene oxide, chitosan, xanthangum, tragacantha, guar gum, acacia gum, arabic gum, carrageenan,pululan, polyacrylic acid, methylmethacrylate copolymer, carboxyvinylcopolymers, and various mixtures of the above and other knownwater-soluble polymers, cellulose derivatives, and/or gums, amongothers. Other polymers that may be used include, but are not limited to,ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetatephthalate, hydroxypropyl methyl cellulose phthalate and combinationsthereof.

In some embodiments, the polymer matrix may include a surfactant toadjust the rate of dissolution and/or the surface energy of the formedconstruct. In other embodiments, the rate of dissolution may be adjustedby the use of a combination of high and low molecular weight polymerswith or without the use of a surfactant. For example, particularlybeneficial properties of film strength and disintegration profile (i.e.the rate at which the construct disintegrates upon contact with the oralcavity or other mucosa) are obtained when the water soluble componentsinclude a combination of low molecular weight polymers (e.g., those lessthan about 5,000 to about 60,000 daltons) and high molecular weightpolymers (e.g., those of about 60,000 to about 150,000 daltons, up toabout 500,000 daltons, or higher).

Various other polymers can be selected by one of ordinary skill in theart given the teachings herein and preferably includes a sufficientamount of a high molecular weight component to impart adequate strengthand a sufficient amount of a low molecular weight component tofacilitate the desired disintegration profile.

Additionally, one may select a single water-soluble polymer as thematrix-forming ingredient with other ingredients that assist withstrength and disintegration, such as surfactants, fillers, andplasticizers. It will further be appreciated that other constituentsuseful in processing may be employed, including rheology modifiers. Anysuitable modifiers may be used including acrylic polymer sodium salts,such as Aculyn by Dow Chemical, which is available in various gradeshaving different molecular weights. The choice of any particularinactive formulation ingredient combination may also be dependent, inpart, on its interaction with the active ingredient(s) and its influenceon the properties of active ingredient(s).

According to another exemplary embodiment of the invention, films andother unit dose constructs using a water soluble low molecular weightcomponent need not use a water soluble polymer for that component.Instead, the low molecular weight component may be other low molecularweight molecules, monomers, oligomers or a combination thereof (i.e.xylitol, glycerol, polyethylene glycol, propylene glycol, etc.). The lowmolecular weight component serves to promote disintegration, but ispresent in an amount such that strength is adequate for processing anddispensing. Various concentrations of the low molecular weight componentcan be utilized.

The amounts of high and low molecular weight components can be adjustedto achieve a desired disintegration profile for the film, which mayrange from a few seconds to several minutes or even hours. When slowerdisintegration is desired, the concentration of the high molecularweight component can be increased relative to the concentration of thelow molecular weight component. When faster disintegration is desired,the concentration of the low molecular weight component can be increasedrelative to the concentration of the high molecular weight component.Additionally, the thickness and surface to volume ratio of the constructcan be adjusted to achieve a desired disintegration profile. To increasethe disintegration time, the thickness is increased and/or the surfaceto volume ratio is reduced. Adequate film strength should be maintainedto allow for handling of the construct.

In addition to the active ingredient discussed immediately below, otheringredients that may be incorporated into the formulation include aplasticizer, sweetener, thickener, buffer, stabilizer, flavorings,and/or other additives and which are preferably, but not necessarily,water soluble. The types and amounts of such ingredients are familiar tothose within the art for formulating dissolvable constructs inaccordance with conventional methods. It will be appreciated, however,that exemplary embodiments, which employ deposition of individual,discrete unit doses, may have an overall solids or non-volatile contentin the formulation that is greater than that used in conventionalmethods and, as a result, require less drying time. Thus, while referredto herein as a liquid formulation that is employed to form theindividual unit doses, it will be appreciated that term encompasses anywet, non-solid flowable substance and in some embodiments may resemblethe consistency of a paste.

Unit dose constructs in accordance with exemplary embodiments alsoinclude one or more active ingredients, typically a pharmaceutical drug.A wide range of active ingredients may be incorporated into the liquidformulation prior to formation and may be incorporated in any form,including as a solution, emulsion, suspension, or dispersion. Thespecific form may depend upon the particular combination of activeingredient and polymer to be employed. That is, active-containing liquidformulations that are used to create the constructs may be in the formof a solution in which all ingredients, including drug substances, arefully dissolved and soluble in the bulk liquid; as an emulsion,typically used for aqueous formulations to which an oil-solubleingredient such as a flavoring has been added; and suspensions ordispersions in which insoluble active ingredients or other excipientsmay be added to the bulk-liquid formulation while still achievinguniformity of distribution in the subsequently formed construct.

Active ingredients include, by way of example and not of limitation,ace-inhibitors, antianginal drugs, anti-arrhythmias, anti-asthmatics,anti-cholesterolemics, analgesics, anesthetics, anti-convulsants,anti-depressants, anti-diabetic agents, anti-diarrhea preparations,antidotes, anti-histamines, anti-hypertensive drugs, anti-inflammatoryagents, anti-lipid agents, anti-manics, anti-nauseants, anti-strokeagents, anti-thyroid preparations, anti-tumor drugs, anti-viral agents,acne drugs, alkaloids, amino acid preparations, anti-tussives,anti-uricemic drugs, anti-viral drugs, anabolic preparations, systemicand non-systemic anti-infective agents, anti-neoplastics, anti-Parkinsonagents, anti-rheumatic agents, appetite stimulants, biological responsemodifiers, blood modifiers, bone metabolism regulators, cardiovascularagents, central nervous system stimulates, cholinesterase inhibitors,contraceptives, decongestants, dietary supplements, dopamine receptoragonists, endometriosis management agents, enzymes, erectile dysfunctiontherapies, fertility agents, gastrointestinal agents, homeopathicremedies, hormones, hypercalcemia and hypocalcemia management agents,immunomodulators, immunosuppressives, migraine preparations, motionsickness treatments, muscle relaxants, obesity management agents,osteoporosis preparations, oxytocics, parasympatholytics,parasympathomimetics, prostaglandins, psychotherapeutic agents,respiratory agents, sedatives, smoking cessation aids, sympatholytics,tremor preparations, urinary tract agents, vasodilators, laxatives,antacids, ion exchange resins, anti-pyretics, appetite suppressants,expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatorysubstances, coronary dilators, cerebral dilators, peripheralvasodilators, psycho-tropics, stimulants, anti-hypertensive drugs,vasoconstrictors, migraine treatments, antibiotics, tranquilizers,anti-psychotics, anti-tumor drugs, anti-coagulants, anti-thromboticdrugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants,neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid andanti-thyroid preparations, diuretics, anti-spasmodics, terine relaxants,anti-obesity drugs, erythropoietic drugs, anti-asthmatics, coughsuppressants, mucolytics, DNA and genetic modifying drugs, andcombinations thereof. The types and amounts of active ingredients to beemployed are familiar to those within the art for formulatingconventional dissolvable films and tablets.

Unlike conventional methods of forming dissolvable thin films as a castsheet that is subsequently cut into smaller unit doses, constructs inaccordance with exemplary embodiments are created by direct depositionof the liquid formulation in discrete regions to form individual unitdoses. Among other advantages, the use of individually formed doseslimits variation of the active ingredient between dosage units that mayoccur across a continuous web as a result of coating thicknessvariations in conventional master roll film formation. This helps ensurethat a relatively more precise, consistent volume of formulation andactive ingredient can be deposited in directly forming smaller-scale,single unit doses.

The direct formation of unit doses may be accomplished using anysuitable technique for accurately and precisely depositing a discreteamount of the liquid formulation (i.e., polymer, active ingredient, andany additives) onto a surface such that each deposition forms its ownindividual, unit dose construct upon drying. Exemplary techniques thatmay be used for the deposition include patch coating, gravure printing,screen printing, stenciling, micro-deposition, and direct dispensing, byway of example only.

FIG. 1 illustrates an exemplary system for carrying out direct formationof unit dose constructs employing a depositor 100 that deposits, via asuitable unit deposition method, the muco-adhesive formulation directlyonto a foil substrate 20 to form unit dose constructs 10, shown here asfilms.

According to certain exemplary embodiments, depositing the film in aunit dose form is accomplished by stenciling, an additive depositionprocess. While all forms of deposition are contemplated, stenciling hasseveral desirable advantages over screen printing and other forms ofdeposition for the formation of individual discrete dosage forms. Oneadvantage is the ability to deliver readily an appropriate depositthickness for the construct being formed. Openings in the stencil maskdefine a volume of paste with which the openings in the stencil arefilled. In comparison to screen printing where a mesh is used to supporta mask and through which a liquid must be transferred, the stencil hasno structure in the opening.

In screen printing the amount of liquid transferred to the substrate isa function of several factors including the percent open area in themesh, the thickness of the photomask used to image the screen, the presssetup (i.e. the force used to push the liquid through the screen) andthe position within the screen from which the liquid breaks from thescreen as it is transferred to the substrate (i.e. in most cases thereis not 100% transfer of the liquid from the screen's mesh). Instenciling, the stencil mask is pressed against the substrate and thesqueegee forces the liquid into the stencil opening. This fills theopening and delivers a liquid column equal to the stencil's thickness.As a result, the use of stenciling also provides a more uniform depositof the construct formulation.

The use of stenciling in accordance with exemplary embodiments to formdissolvable thin films and other unit dose constructs is novel andintroduces various challenges and concerns not faced in other,conventional, stenciling applications, but which are overcome inaccordance with exemplary embodiments. Similarly, methods of directlyforming individual unit doses also present challenges not present withconventional wide roll production methods of dissolvable thin films.

The equipment used for stenciling of the unit doses may be any knowntype used in conventional stenciling applications and generally includesa stencil frame, fill blade or squeegee, vacuum table, and a press thatcontrols the process.

In embodiments employing stenciling, a sheet of material, typicallyconstructed of a metal, is attached to a frame, to suspend the sheetfrom the frame about its perimeter. The desired image corresponding tothe shape of the construct to be created is cut or etched from the sheetto form a stencil having a totally-open image. The open space is thenfilled with the liquid formulation (typically a paste) using a fillblade or squeegee moving across the open stencil. The thickness of thesheet of material for stenciling may be selected to correspond to thethickness of the film or other construct to be created with the stencil.

FIG. 2 schematically illustrates this stenciling processing, showing atable 210 or other support, which may be disposed within the depositor100 (FIG. 1). A stencil 220, attached to a frame 230, which is placedagainst a substrate (in this case the foil 20), while a squeegee 240 isused to spread a paste 250 of the muco-adhesive formulation into theopenings formed in the stencil 220. Thereafter, the stencil is removed,leaving behind the paste 250 in the form of unit dose constructs 10 onthe foil 20.

In the case of stenciling for the deposition of films or otherconstructs in individual dosage forms, the liquid muco-adhesiveformulation is a composition that typically has a high solids contentwith a low amount of liquid carrier, with the consistency of a paste orgel. The paste is generally a thixotropic fluid with a predeterminedrheology. It will be appreciated that the characteristics of aparticular paste may depend upon the constituents in the formulation, aswell as the shape, size and thickness of the construct to be formed.Generally, the viscosity is in the range of about 20,000 cps to about500,000 cps, in some embodiments, in the range of about 20,000 cps toabout 180,000 cps. Shear rates can vary, but are typically in the rangeof about 0.05 s⁻¹ to about 10 s⁻¹.

The use of a thixotropic paste is preferred as it means little or noflow occurs except when forced into the stencil by the squeegee. Thisenables the unit dose to better hold its shape after the stencil isremoved. This helps control product uniformity in all types ofconstructs and is particularly advantageous when unit dose constructsare formed as thick films, wafers or tablets.

Regardless of the specific type of stenciling equipment employed, insetting up the equipment, the vacuum table should be of a uniformflatness. Preferably the flatness has a tolerance at least as fine as+/−0.0010 inches.

Care should also be taken in set-up to ensure proper positioning of thestencil relative to the substrate. As part of further set-up, the pressis adjusted so both the peel and off-contact are set at or near zero forstenciling deposition of the individual unit doses. That is, anynecessary adjustments should be made so that the frame of the stencildoes not rise during the travel of the squeegee (i.e., “peel”) and sothat the stencil is in direct contact with the desired substrate (i.e.,no “off-contact”).

The squeegee or other blade employed in the process may be constructedof metal or any other suitable material including stainless steel orpolyurethane, for example. To ensure consistent unit size (and thusconsistent delivery of the active ingredient to be delivered) the bladeshould be straight, even and level with a uniform thickness and/ordurometer hardness across its entire length. When using a polyurethanesqueegee, a squeegee with a double bevel cut is preferred to yield amore uniform deposition.

It will be appreciated that the angle of the squeegee cut along thedeposition angle may vary depending on the desired unit dose thickness,as well as the rheology of the paste formulation being used. It willfurther be appreciated that the edge definition, as well as the evennessof the paste's deposition may be dependent upon both squeegee pressureas well as the speed of travel of the squeegee across the image.

Returning to FIG. 1, which illustrates an exemplary system for carryingout the stenciling in which the stenciling (or other method ofdeposition) occurs within the depositor 100 that deposits theformulation directly onto a foil substrate 20 to form unit doseconstructs 10, illustrated here as films as previously noted. The foilsubstrate 20 may advantageously be the same material that serves asprimary packaging for the construct 10, which emerges from the depositor100. The foil substrate 20 and constructs 10 may be transported along aconveyor 200. In other embodiments, the use of rolled foil may obviatethe need for the conveyor by simply winding or unwinding the roll.

After the formulation has been stenciled onto the foil substrate 20, theliquid carrier in the formulation is driven off by any suitable methodto yield the dissolvable construct 10. Exemplary drying methods include,but are not limited to, exposure to ambient air, infra-red (IR) heating,ultrasonic, vibration, microwave, forced air and/or hot-air systems andcombinations thereof.

A benefit of depositing individual unit doses directly onto thepackaging material is the ability to vacuum dry the liquid (or paste inthe case of stencil deposition) formulas to form the film or other formof construct. The use of vacuum drying provides faster drying times atlower temperatures that, in-turn, affords improved productivity, lowerenergy consumption (less heat) and improved construct and drug stabilityas a result of the lower temperatures. Vacuum drying also yields abetter content uniformity and patient dosing by reduced potential forentrapped air or bubble defects. Improved productivity can be achievedby drying more quickly at lower pressures as well as affordingintegration of other product conversion steps as part of an overall,in-line process sequence. As with other drying methods, vacuum dryingmay be carried out contemporaneously with one or more of the otherdrying methods previously discussed. Additionally, in some embodiments,vacuum drying is carried out in combination with cooling, to achieve alyophilization effect on thicker constructs, such as tablets. Asreferred to herein, vacuum drying means any pressure less than ambientatmospheric, including zero torr. That is, vacuum drying encompassesboth partial and full vacuum.

Vacuum drying is not used with drying conventional thin film manufacturefor a variety of reasons. Conventional techniques employ relativelywide, long, continuous rolls of paper or polymeric film (e.g. polyester)release liners and the process is a continuous, constantly moving web.Accordingly, for a vacuum to be achieved the film must be encapsulatedand sealed from the surrounding environment for air to be effectivelyevacuated. Because the coated web is continuously in motion during theformulation coating and subsequent drying process, encapsulation and airremoval are not feasible in conventional thin film coating processes.Furthermore, the backing substrates or release liners typically employedmay not serve as an effective air barrier thereby compromising theencapsulation effectiveness, particularly for paper release liners. Theinherent flexibility of conventional release liner coating substratesadversely affect the quality of the thin film coatings during airevacuation for lack of enough mechanical integrity or stiffness toprevent distortion as air is removed by the vacuum pump.

Exemplary embodiments are not so limited and vacuum drying techniquesare readily employed. In one embodiment, individual thin film unit doseconstructs are stenciled in an array on a stationary but continuous webof packaging foil as described with respect to FIG. 1. Followingdeposition of that array by stenciling, the web is advanced apre-determined distance upon which another array is then formed bystenciling on the web at a different location. While the second array isbeing deposited, a vacuum encapsulation fixture is lowered over thefirst array using the packaging foil as the base of the enclosure withinwhich vacuum is applied. Some heat may also be applied if needed ordesired. After deposition of the second array and drying of the first,the vacuum is relieved and the encapsulation fixture is raised orremoved. The web is advanced and the process proceeds in astep-and-repeat manner, with the second array subjected to vacuum dryingwith the encapsulation fixture while a third layer is stenciled.

It will be appreciated that the packaging foil may be held in placeduring the encapsulation process to reinforce it against collapse whenthe vacuum is applied. For example, application of a vacuum may beapplied to the opposite, underlying side of the foil (i.e., oppositefrom that on which the formulation was deposited). The resulting appliedsuction may be accomplished, for example, using an array of holes in aflat metal plate that firmly holds the foil in place prior topositioning of the vacuum fixture and vacuum application.

After the films or other form of unit dose constructs 10 are dried, atop layer of foil (not shown) or other packaging material is applied toprotect them prior to use. Although the constructs are individuallyformed, the foil substrate and the top layer of foil are typicallycontinuous webs that can thereafter be sealed and cut into individualpackages, each containing a single construct.

Regardless of the specific drying method used, it is advantageous tocarry out the drying step in a controlled atmosphere. In certainembodiments, the drying is conducted in a nitrogen or other reducedoxygen or oxygen free environment. Reducing exposure to oxygen providesthe benefit of limiting oxidative degradation to which many activepharmaceutical ingredients are susceptible, resulting in greaterstability of the formed construct. Such an environment may be achieved,for example, by processing in a nitrogen filled production setting (e.g.while drying) or by directing a flow of nitrogen gas over the constructs10.

In other embodiments, in combination with or separate from the use of anitrogen environment, the controlled atmosphere includes maintaining alow humidity throughout film processing. A relative humidity of below45%, typically 40% and more preferably below 35%, results in theconstructs having less tack, aiding in the ability to be more easilyremovable from their package.

Yet another advantage of stenciling is that the rheology does not haveto be tuned to produce a level deposit. In screen printing, the liquidfilm formulation must move through the mesh openings, then flow outafter the screen moves away to produce a smooth deposit across theimage. Failure to flow would result in screen mesh marks appearing inthe deposit. In stenciling, the squeegee itself acts to level thedeposit of the formulation as it moves across the opening.

Furthermore, the generation of an aesthetically acceptable deposit interms of its appearance is readily accomplished with stenciling. Movingliquid film formulations across a mesh screen results in a significantamount of air being entrained in the fluid that remains when thedeposited film formulation is cured. With stenciling, this issue isminimized because the liquid, or paste, is pushed across a smoothstencil plate. Additionally, screen printing is usually done by pushingthe liquid across the screen twice to deliver a screen printed image(flood/print), while the liquid is pushed across the stencil only oncefor stenciling (print/print).

The deposition of individual, discrete unit doses by stenciling orotherwise also affords the possibility of an infinite number of designshapes. In particular, design shapes that enhance disintegration timesbut without yield loss or additional cost associated with die cuttinginto those shapes can be achieved, as well as the ability to formcomplex shapes that would be impractical or impossible to form bydie-cutting. For example, a film or other type of unit dose constructmay be directly formed as a donut or oval with a hole in the center thatincreases the surface area of the film available for dissolution bysaliva. In other embodiments, simply providing more traditional shapedrectangular constructs, but with rounded edges aids in removability fromthe package.

Another advantage that can be achieved with exemplary embodiments is theability to create a product that corresponds to a particular regimen inwhich, for example, a multi-week supply of a particular product isprepared at once. For example, if the regimen calls for variations instrength depending upon the day, a row of seven can be deposited withthe size of each film or other construct 10 within that row varied basedon the called upon regimen as illustrated in FIG. 1A, which shows fourrows of seven films (i.e. four weeks), with a variation in size in therow corresponding to the amount required on a particular day. Eachregimen may then be sealed, segregated and marked; the regimen may beformed as a single packet 11 with individual packages separately sealingthe films of the regimen, the packages being separable from one another,such as by perforation, for later separation and opening by the user.

Yet another advantage associated with exemplary embodiments is theavoidance of yield losses associated with conventional dissolvable filmproduction processes. Current continuous master roll production used inconventional processes includes start-up and end-of-roll losses that, ona percentage basis, increase as the coating length is reduced.Furthermore, the master roll typically has an edge that has to betrimmed and removed in a post-coating, roll-slitting process. Additionalyield losses occur when the slit rolls are subjected to a die-cuttingprocess to produce the individual finished unit doses. There arestart-up losses during the die-cutting and packaging process as themanufacturer sets up the machine to coincide with unit placement andheat-sealing of the individual primary package. Because the formulationsused to create the film generally contain relatively expensivepharmaceuticals, these yield losses represent a significant cost.

Accordingly, by forming individual unit doses in accordance withexemplary embodiments, these types of yield losses are avoided.Furthermore, reconciliation for controlled substances is easier;diversion of controlled substances becomes more obvious and recognizablein the manufacturing supply chain because less of the controlledsubstance is lost as waste in the trimming process that can introducedifficulty in accounting for other sources of drug loss.

As briefly noted earlier, conventional methods of dissolvable thin filmproduction use a master roll cast onto a paper or polyester substrate(with or without a release layer) that serves purely as an in-processand handling aid that adds no direct product value. Instead, itrepresents an additional cost as the liner is removed and discardedduring downstream die-cutting of the individual dosage units from themaster roll. Exemplary embodiments eliminate the need for the linerprocessing aid, as well as the slitting and individual dosage unit diecutting steps. Instead, individual unit doses of the liquid formulationcontaining the active ingredient are deposited directly onto the foilsubstrate 20 that is the ultimate packaging material. Unit dosepackaging may be accomplished directly after unit dose deposition anddrying as an extension of the unit dose deposition process.

In some exemplary embodiments, the releasability of the unit doseconstruct 10 from the packaging foil (i.e. the foil substrate 20) isenhanced. One manner in which this is achieved is by providing a surfacetreatment and/or release coating on the surface of the foil substrate 20to which the constructs 10 are deposited. Exemplary surface treatmentsinclude a laminate foil having a layer applied to its surface composedof a material that is tailorable to exhibit different levels of surfaceenergy via, for example, chemical composition or treatment. An examplesof such materials includes polyethylene homopolymer and ethylene vinylacetate (EVA) copolymers ranging from 100% polyethylene to 60%polyethylene/40% vinyl acetate (by weight), in which the surface energyis modified by adjusting the amount of vinyl acetate present in thecomposition. Surface energy may also be tailored by subjecting the foil(or foil laminate) to radiation, corona discharge, plasma, or otherknown techniques for modifying surface energy. The surface energymodification can be over the entire substrate surface or over one ormore distinct regions may be applied in a repeating pattern or atspecific, discrete locations.

Turning to FIG. 3, in one embodiment a unit dose construct 10 is formedon the foil substrate 20 that forms the bottom of the package asdescribed above with respect to FIG. 1. While the entire foil substrate20 may include a release coating or other surface treatment, in thisembodiment a smaller region 22 (shown in cross-hatch for purposes ofillustration) of the foil substrate 20 has a release coating or surfacetreatment that results in construct adhesion in that region 22 that islower than the rest of the substrate 20.

The package is sealed by a top foil layer 30 applied over the construct10 to form the package and seal it from the surrounding environment. Thetop foil layer 30 may also be surface treated or have a release coatingover its entirety or in one or more identified regions. Like the foilsubstrate 20, the top foil layer 30 is also illustrated with a region 32(shown in cross-hatch for purpose of illustration) with a surfacetension that differs from the rest of the top foil layer 30 byemploying, for example, a different release coating or a different typeor amount of surface treatment. In this embodiment, that region 32 isthe only portion which has any adhesion to the construct 10 and thatadhesion is greater than that of the construct to the foil substrate 20.

As a result, when the top layer 30 and the foil substrate 20 (whichwould be overlying one another to form the package, but are shownside-by-side for purposes of illustration and discussion) are separatedfrom one another by an end user, removing the top layer 30 from the foilsubstrate 20 lifts the construct 10 from the foil substrate 20. Thishelps the user easily grasp and remove it from the package.

It will be appreciated that FIG. 3 shows a separated single unit dosepackage for purposes of illustration. In the context of the continuousprocess illustrated in FIG. 1, the roll of foil used for the foilsubstrate 20 is provided with regions of differing surface tensionestablished in advance according to a particular pattern that achievesthe desired result, which may be specific to the size and otherparameters of the construct 10 being manufactured, and thus where it isdeposited on the substrate 20 with respect to those regions.Alternatively, the surface energy modifications, tailoring or patterningcan be accomplished as an integral part of the deposition process, i.e.,as part of an inline treatment process of the foil during constructproduction.

Alternatively, or in combination, the surface energy of the formulationbeing deposited can also be modified or tailored to achieve a desiredrelease characteristic after deposition.

The modification of surface energies of the substrate and/or theformulation is primarily with respect to release characteristics, as theuse of a thixotropic paste in forming the unit doses results in low flowin the absence of a shear force. Nevertheless, in some embodiments,surface energy modification may also be employed to result in betterwetting by the unit dose formulation. In one embodiment, a corona- orplasma- treatment using the stencil prior to formulation provides aregion on the substrate surface of increased surface energy thatpromotes fluid migration. In another embodiment, the surface energy ofthe formulation being stenciled can be modified or tailored to achieve adesired flow characteristic during and after stenciling.

In addition to improvements in the manufacturing of thin films and otherunit dose constructs, the use of stenciling or other unit depositionmethods to deposit discrete amounts of the formulation also provides anability to achieve improvements in the unit dose constructs themselves.

Some drug delivery films employ a two layer film in which a first layercontains a formulation containing the active ingredient and a secondlayer serves as an inactive backing layer or a layer containing adifferent active ingredient or the same active ingredient at a differentconcentration. The second or backing layer may be the same or adifferent formulation as the first layer, except that it does nototherwise contain the same active ingredient or same level of activeingredient found in the first layer. The backing layer may serve as abarrier against flow of the active ingredient into the oral cavity andthe gastro-intestinal tract. A significant drawback to making such filmsin the conventional manner is that their wide web production processrequires the first and second layers to be of the same area, formed asoverlying webs in which one of the layers is coated via a second,separate casting or laminating step on top of the other layer.

In addition to requiring first and second layers of the same area, thisprocess also still results in a master roll that requires slitting intonarrower width roles coupled with removal of the beginning and end ofthe rolls to achieve defect-free slit rolls of uniform coated layerthickness. These same considerations apply to situations calling formore than two layers.

Exemplary embodiments employing unit dose deposition overcome thesedrawbacks by providing a multi-layer film or other unit dose constructthat includes stenciling a smaller area of the active layer within alarger area defined by the backing layer (ordinarily following anintermediate drying step). This can be used to create a window orpicture frame effect as shown in FIG. 4, in which the illustrated film10 is multiple layers, containing an underlying backing layer 12 and asmaller, overlying active layer 14. The backing layer 12 thus provides aperipheral seal around the active layer 14 when the film 10 is appliedto mucosa. This can prevent leakage of the active ingredient from theperiphery of the active layer 14 into the oral cavity and further helpsto ensure that all of the drug or other active ingredient is deliveredvia the desired mucosal pathway.

In addition, the use of the window frame can be used to effectively sealthe active layer 14 and thereby mask an offensive taste due to theactive ingredient. The backing layer 12 prevents leakage of the drugfrom the active layer 14 into the oral cavity where perceptible tastewould occur.

A further advantage over conventional two layer films is that bydepositing the active layer 14 in discrete unit doses onto the backinglayer 12, enhanced dose accuracy and uniformity between films or otherconstructs 10 is achieved because a consistent, precise volume of theactive liquid construct formulation is applied independent of area orthickness of the backing layer.

Conversely, in conventional wide web film manufacture, depositionthickness characterization is typically accomplished by characterizingthe weight deposited per unit area (i.e. “coating weight” sampling);while process parameters are typically adjusted at the front end of acoating campaign and then maintained after the desired target isachieved, the precision of the coating weight of the active layer isaffected by variability in the thickness of the underlying backinglayer. For example, a depression in, or thinning of, the backing layerwould result in a localized area of greater thickness of the activelayer. This concern can be overcome in certain exemplary embodimentsbecause each active layer 14 may be individually measured and stenciledas a consistent volume regardless of any variation in the backing layer12 to which it is applied. It will further be appreciated that exemplaryembodiments may also be used to deposit discrete active layers onto abacking layer that is a continuous web, although that would have theeffect of re-introducing certain trimming and other conversion steps inmanufacturing.

Stenciling the active layer 14 as an individual unit dose toindividually formed backing layers 12 also affords flexibility thatpermits variation in the size of the active layer 14 within the areadefined by the backing layer 12. Turning to FIGS. 5A and 5B, in certainembodiments different dosage strengths can be achieved by depositingsmaller or larger active layers 14 a,b on the backing layer 12. Thus,the same size backing layer 12 can be used to deliver the same sizeconstruct 10 across multiple dosage strengths. Conversely, the same sizeactive layer 14 can be used with different sized backing layers 12 thatcan be modified to meet a particular class of users' ability to handlethe unit dose construct, particularly in the context of films, which maybe independent of the amount of active ingredient to be employed (i.e.,larger films may be desired for pediatric or geriatric patients). Thismay also be of particular benefit for low dosage and/or particularlypotent drugs which, if used alone without a backing layer, would requirea unit dose area so small that the resulting unit dose construct wouldotherwise be too difficult to handle.

As shown in FIGS. 5A and 5B, two constructs 10 are formed with auniformly sized backing layer 12. In the first construct 10, a smallactive layer 14 a is applied to the backing layer 12, for example, foruse in a pediatric size dose of the active ingredient that in thecontext of this example, still provides a film that, by virtue of thesize of the backing layer 12, is large enough to be easily handled. Foran adult size dose, that same backing layer 12 is used with a largeractive layer 14 b deposited thereon to deliver a larger amount of theactive ingredient, with the same size film. Because the area of theactive layer can be adjusted, the same formulation can be used for boththe pediatric and the adult dose.

An additional benefit achieved by exemplary embodiments that use thesame size backing layer 12 for active layers 14 a, 14 b of differentsize is standardization of the overall construct size across multipledosage strengths. As a result, tooling and packaging can also bestandardized with respect to the same overall size defined by the areaof the backing layer 12.

It will be appreciated that in some embodiments, it may be desirable toincorporate additional ingredients into the active layer formulationsused to produce active layers 14 a, 14 b of different dosage strengthsto more easily differentiate between them. For example, while theoverall size of the doses containing the active layers 14 a, 14 b may bedifferent, they might still be visually similar. Differentiation may beachieved, for example, by the use of different colors for active layersof different strengths. Colorants may also be used to distinguish films10 or other unit dose constructs having different active ingredients,even if the size or strength of the dosage is the same.

FIG. 6 illustrates yet another exemplary embodiment. In some cases, twoactive-drugs must be conveyed to a recipient at the same time. This maybe achieved by combining two different active ingredients in theactive-layer formulation. However, that combination may not be possiblein many circumstances such as, for example, where the active ingredientsare incompatible (e.g., they react or degrade when in contact with oneanother).

Exemplary embodiments of the invention overcome this problem byproviding a construct 10 that employs a single backing layer 12 on whichmultiple different active layers 14, 16, 18 containing different activeingredients can be separately and individually stenciled in discreteregions of the backing layer 12. This maintains separation betweenincompatible active ingredients, which can thus be isolated from oneanother up to the point of administration (i.e., ingestion, etc.).

Another advantage of exemplary embodiments, which provide for theproduction of unit dose constructs containing two or more layers andincluding different APIs positioned adjacent one another in the sameconstruct is that such an approach is not possible in conventional meansof forming orally disintegrating tablets (ODTs) such as tablet pressingand/or lyophilization. If a tablet coating is applied, it will surroundthe tablet core by traditional manufacturing methods. This does notallow for maintaining two separate layers that provide unidirectionaldrug release.

EXAMPLES

The invention is further described by way of the following examples,which are presented by way of illustration, not of limitation.

Example 1

An aqueous placebo formulation was formed with 19.4% solids includingthe following ingredients: hydroxypropyl methylcellulose, polyethyleneoxide, disintegrant, buffering agents, sweetener, flavor and a colorant.The viscosity when it was measured using a small-sample Brookfieldspindle was found to be approximately 57,600 cps at 4 s⁻¹.

Example 2

The formulation in Example 1 was dispensed directly onto a foilsubstrate (Alcan DM8964 peelable foil) using a stencil and a stencilpress. The stencil thickness was 0.035″. Stencil openings were 1″×2″ inan 18-up format. Once the formulation was deposited onto the foil, itwas dried using a gas forced-air oven at 70° C. for 8 minutes.

Example 3

An aqueous formulation was formed with 22% solids including thefollowing ingredients: hydroxyethyl cellulose, hydroxypropyl cellulose,buffering agents, sweetener, flavor, preservatives and colorant. Theviscosity when it was measured using a small-sample Brookfield spindlewas found to be approximately 25,000 cps at 0.05 s⁻¹.

Example 4

An aqueous formulation was formed with 11% solids including thefollowing ingredients: sodium carboxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, polyacrylic acid, buffering agents,sweetener, flavor, preservatives and an active ingredient. The viscositywhen it was measured using a small-sample Brookfield spindle was foundto be approximately 12,000 cps at 0.05 s⁻¹.

Each of Examples 3 and 4 were also formed into unit dose constructs asdescribed in Example 2.

While the invention has been described with reference to particularembodiments, it will be understood by those skilled in the art thatvarious changes may be made and equivalents may be substituted forelements thereof without departing from the scope of the invention. Inaddition, many modifications may be made to adapt a particular situationor material to the teachings of the invention without departing from theessential scope thereof. Therefore, it is intended that the inventionnot be limited to the particular embodiment disclosed as the best modecontemplated for carrying out this invention, but that the inventionwill include all embodiments falling within the scope of the appendedclaims and all other patentable subject matter contained herein.

1. A method of forming a dissolvable unit dose construct comprising: providing a muco-adhesive composition comprising a polymer matrix, the polymer matrix comprising a water soluble polymer, the composition further comprising an active ingredient and a liquid carrier, the composition in the form of a thixotropic paste; stenciling the paste onto a substrate to deposit the composition as a plurality of individual dosage units; and removing at least a portion of the liquid carrier from the individual dosage units.
 2. The method of claim 1, wherein the step of stenciling deposits the paste onto a substrate in a predetermined geometric shape having at least three sides.
 3. The method of claim 2, wherein the predetermined geometric shape includes a rounded corner.
 4. The method of claim 1, wherein the substrate is a foil substrate.
 5. The method of claim 4, wherein the foil substrate is a treated foil substrate having a modified surface energy on a surface facing the deposited composition.
 6. The method of claim 5, wherein a first area of the treated foil substrate has a modified surface energy on the surface facing the deposited composition that is lower than a surface energy of a second area of the surface of the treated foil substrate facing the deposited composition.
 7. The method of claim 1, wherein the water soluble polymer comprises cellulose or a derivative thereof.
 8. The method of claim 1, wherein the active ingredient comprises a pharmaceutical drug.
 9. The method of claim 1, wherein the muco-adhesive composition is provided as a paste having a viscosity in the range of 20,000 cps to 500,000 cps at a shear rate in the range of 0.05 s⁻¹ to 10 s⁻¹.
 10. The method of claim 1, wherein the step of removing comprises removing at least a portion of the liquid carrier by vacuum drying.
 11. The method of claim 10, wherein the step of removing further comprises, contemporaneously with vacuum drying, removing at least a portion of the liquid carrier by heating, cooling, ultrasonic, vibration or a combination thereof.
 12. The method of claim 1, further comprising depositing a second composition, after the step of stenciling, to form multi-layered individual dosage units.
 13. The method of claim 1, comprising depositing adjacent individual unit doses having different areas.
 14. The method of claim 1, wherein the individual dosage units are dissolvable films.
 15. The method of claim 1, wherein the individual dosage units are tablets or wafers.
 16. The method of claim 1, wherein the step of removing is carried out in an atmosphere having a lower oxygen content than air.
 17. The method of claim 1, wherein the step of removing is carried out in an atmosphere having less than 45% relative humidity
 18. A method of forming a dissolvable unit dose construct comprising: providing a muco-adhesive composition comprising a polymer matrix, the polymer matrix comprising a water soluble polymer, the composition further comprising an active ingredient and a liquid carrier; depositing the composition onto a substrate as a plurality of individual dosage units; and vacuum drying the individual dosage units to remove at least a portion of the liquid carrier.
 19. The method of claim 18, further comprising drying the composition by the application of heat, vibration, ultrasound, or a combination thereof contemporaneously with the step of vacuum drying.
 20. The method of claim 18, wherein the substrate is a foil substrate.
 21. The method of claim 20, wherein a second vacuum is applied to an opposite side of the foil on which the composition is deposited, the second vacuum applied contemporaneously with the step of vacuum drying.
 22. The method of claim 20, wherein the foil substrate is a treated foil substrate having a modified surface energy on the side on which the composition is deposited.
 23. The method of claim 20, wherein a first area of the treated foil substrate has a modified surface energy on the side on which the composition is deposited that is lower than a surface energy of a second area on the side of the treated foil substrate on which the composition is deposited.
 24. The method of claim 18, wherein the step of depositing comprises stenciling.
 25. The method of claim 24, wherein the composition is provided as a thixotropic paste having a viscosity in the range of 20,000 cps to 500,000 cps at a shear rate in the range of 0.05 s⁻¹ to 10 s⁻¹.
 26. The method of claim 17, further comprising, after the step of depositing, depositing a second composition to form multi-layered individual dosage units.
 27. A method of forming a dissolvable unit dose construct comprising: providing a first composition comprising a water soluble polymer and a liquid carrier; depositing the first composition onto a substrate; providing a second composition comprising a water soluble polymer and a liquid carrier; stenciling the second composition at a plurality of discrete locations overlying the first composition; and removing at least a portion of the liquid carrier from the first and second compositions to form a multi-layer unit dose construct.
 28. The method of claim 27, further comprising removing a portion of the liquid carrier from the first composition intermediate the steps of depositing and stenciling.
 29. The method of claim 27, comprising forming a first multi-layer unit dose construct and thereafter forming a second multi-layer unit dose construct, wherein the first multi-layer unit dose construct contains a volume of the second composition greater than the second multi-layer unit dose construct.
 30. The method of claim 29, wherein the first and second individual units contain a same volume of the first composition.
 31. The method of claim 29, wherein the first and second compositions are formed as films.
 32. The method of claim 27, comprising depositing the first composition on the substrate as individual units.
 33. The method of claim 27, wherein the second composition further comprises an active ingredient.
 34. The method of claim 27, wherein the first composition further comprises an active ingredient.
 35. The method of claim 27, wherein the step of removing comprises vacuum drying.
 36. The method of claim 27, further comprising providing a third composition comprising a water soluble polymer and a liquid carrier; depositing the third composition overlying a portion of the first composition, wherein a first multi-layer unit dose construct comprises the first and second compositions and a second multi-layer unit dose construct comprises the first and third compositions.
 37. The method of claim 36, wherein the first individual unit dose construct consists of the first and second compositions and the second individual unit dose construct consists of the first and third compositions.
 38. A method of forming a dissolvable unit dose construct comprising: providing at least one muco-adhesive composition comprising a polymer matrix, the polymer matrix comprising a water soluble polymer, the composition further comprising an active ingredient and a liquid carrier; depositing the composition onto a substrate as a first individual dosage unit; depositing a second individual dosage unit onto the substrate adjacent the first individual dosage unit; and removing liquid carrier from the individual dosage units, wherein the first and second individual units are distinct from one another.
 39. The method of claim 38, wherein the first and second individual dosage units are formed of the same muco-adhesive composition, the units distinct from another in unit volume.
 40. The method of claim 38, wherein the first and second individual dosage units are distinct in chemical composition.
 41. The method of claim 38, wherein the first and second individual dosage units are distinct in color.
 42. A method of forming a dissolvable unit dose construct comprising: providing a first composition comprising a water soluble polymer and a liquid carrier; depositing the first composition onto a substrate to form a plurality of individual units; providing a second composition comprising a water soluble polymer, an active ingredient and a liquid carrier; depositing the second composition overlying a portion of an individual unit of the first composition; providing a third composition comprising a water soluble polymer, an active ingredient of an identity different from the active ingredient of the second composition, and a liquid carrier; depositing the third composition overlying a portion of the individual unit of the first composition different from the portion overlain by the second composition; and removing at least a portion of the liquid carrier from the compositions to form a multi-layer unit dose construct.
 43. The method of claim 42, wherein the second and third compositions are differentiable by color.
 44. The method of claim 42, wherein the step of removing comprises vacuum drying.
 45. The method of claim 42, wherein at least one of the depositing steps is accomplished by stenciling.
 46. The method of claim 42, wherein the area of the second composition overlying the first composition is greater than the area of the third composition overlying the first composition. 